The use of idiotype specific antibodies, ie, anti-idiotypic antibodies, as immunogens is based on the rationale put forward by the idiotype-network theory (Jerne, N K, Eur J Immunol 34:1243-50, 2004; Jeme, N K, et al., EMBO J 1:243-7, 1982). According to this theory, an antigen (Ag) induces an Ab (Ab1) specifically recognizing a defined amino acid sequence and/or structural motif unique to the Ag.
Because the Ag-binding sequence of Ab1 is unique, Ab1 is seen as foreign by the immune system which has produced it. As a consequence, the immunized host generates another Ab (Ab2), which recognizes specifically the Ag-binding sequence of Ab 1. Since only certain areas (the idiotopes) of Ag-binding regions of antibodies differ between Ab1 and antibodies of other specificities present in the host, it is believed that Ab2 recognizes only the Ag-binding sequence on Ab1. Therefore, the Ag binding sequence of Ab1 recognizes several amino acids of the Ag, and it is therefore generally believed that Ab2 carries the “internal image” of the Ag. (Jerne, N K, Eur J Immunol 34:1243-50, 2004; Jerne, N K, et al., EMBO J 1:243-7, 1982). Based on this rationale, a number of immunotherapy studies have used Ab2 as an anticancer agent (Pride, M W, et al., Clin Cancer Res 4:2363-70, 1998). However, the role of idiotype-specific immune responses in regulation of tumor proliferation and metastasis is poorly understood.
One hypothesis is that Ab2 stimulates the immune system to generate new antibodies to the “internal image” of the Ag. These Ab, generally termed Ab3, once induced, will interact with the inducing Ag on the tumor cell with higher affinity than Ab 1. However, the question is more complex than it initially appears. For example, if the tumor Ag and the Ab2 share linear sequence homology, then the resulting T cells, as self-reactive T cells, should be tolerized or deleted.
While the basis of structural mimicry between an Ag and the corresponding anti-id antibody is unclear, one possibility is represented by the structural basis of the interactions of a tumor associated antigen (TAA) and corresponding anti-id antibody with the same area of the antigen combining site of the anti-TAA antibody. These interactions are likely to involve side chains of amino acids which can form strong H-bonds (involving OH groups) and even stronger electrostatic interactions between positively/negatively charged terminal groups of the side chains and reversely charged groups in Ag-binding regions of Ab and of TCR. However, peptides derived from TAA are all generally weak inducers of CTL response (Waters, S. J., et al., Cell Immunol., 111:87-93, 1988).
Thus, to pursue novel immunotherapeutic approaches to the treatment of cancer, there is an ongoing need for determining peptide sequences that can elicit a CTL response against a particular antigen, where the peptides stimulate a CTL response that is greater than the CTL response stimulated by a peptide derived from the antigen.